Tablets and capsules are among the most frequently employed drug dosage forms for delivering active pharmaceutical ingredients (“APIs”). This is because these dosage forms allow for an accurate and easy administration of APIs. Furthermore, handling and packaging, shelf life, and stability of these preparations are generally easier and better than those of other formulations.
To manufacture tablets and capsules, a solid bulk of granulate mass is typically formed by using one of two processes, wet granulation and or dry granulation, and the granulate mass is then compressed into tablets or filled into capsules. Tablets may also be manufactured using direct compression. See, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publishing Co., Easton, Pa., pages 1576-1598 (1975).
In wet granulation, components are mixed and granulated using a wet binder. The wet granulates are then sieved, dried and optionally ground prior to being compressed into tablets or filled into capsules. Wet granulation is used extensively in the pharmaceutical industry although it has proven to be a difficult method, mainly because the liquids needed in the granule may have an adverse effect on the characteristics of the APIs and the stability of the tablets and capsules. For instance, variations in the moisture content of starch used in the manufacturing process may cause the tablets and capsules too hygroscopic or having a reduced shelf life.
Dry granulation is a method of controlled crushing of precompacted powders by either slugging or passing the material between two counter-rotating rolls. Typically, powdered components are mixed prior to being densified by passing the material between two counter-rotating rolls to yield hard slugs, which are then ground and sieved before final production to form tablets or capsules. Substantially no liquids are used in dry granulation. As such, the issues related to wet granulation are avoided. However, dry granulation has not been widely used because of the challenges in producing desired granules as well as managing granulated material in the manufacturing process.
Direct compression requires two principal steps: i.e., mixing the ingredients and compressing the mixture into tablets. Direct compression is considered to be the simplest and the most economical process for producing tablets. However, it may only be applied to a relatively small number of substances that do not need granulation before tableting. Moreover, it is a challenge to find a formulation having an optimal combination of APIs and excipients such that, after mixing, they exhibit desired compressibility, homogeneity and flow-ability for direct compression. Consequently, direct compression has not been widely used in the drug manufacturing processes.
Depending on how APIs are processed into tablets, the physical properties, drug release pattern, and stability of the tablets may be different. For dry granulation and direct compression processes, a small change in drug compositions, or even a change in the order of mixing the components of the same drug composition, may cause segregation and flow-ability problems during the processes, and affect the dissolution and stability profiles of the tablets.
For certain medications, it is required that tablets providing a high dosage of APIs. It is also required that such tablets have fast dissolving immediate release properties. Fast dissolving immediate release properties refer to that the tablet will dissolve in water or aqueous solutions or upon oral administration within a few minutes, preferably within seconds, to produce a clear or almost clear solution.
Fast dissolving immediate release tablets are not easy to manufacture and generally not very stable. Wet granulation is currently the primary method for preparing fast dissolving immediate release tablets. But this method is not ideal because APIs and excipients of fast dissolving immediate release tablets are typically hygroscopic. Consequently, problems such as punch filming, picking and sticking during granulation and compression often occur, which makes the manufacturing processes complicated and time consuming. Making high dosage strength tablets that have fast dissolving immediate release properties are ever more challenging because less excipients are used in the drug compositions, which make it harder to achieve the desired compressibility, homogeneity and flow-ability.
One high dose, fast dissolving immediate release pharmaceutical drug is CARBAGLU tablet, an orphan drug indicated as an adjunctive therapy for the treatment of acute hyperammonemia and for maintenance therapy for chronic hyperammonemia, due to patients' deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). In its drug package insert, CARBAGLU tablet is presented as fast dissolving tablet containing 200 mg of (2S)-2-(carbamoylamino)pentanedioic acid (also known as carglumic acid) as an active compound. It is instructed that that CARBAGLU tablet must be dissolved in 2.5 mL of water and administrated immediately to a patient either orally or through a nasogastric tube. CARBAGLU tablet cannot be swallowed whole or crushed. Otherwise it may cause serious adverse effects to the brain or even cause death. Therefore, it is important that CARBAGLU tablet is fast dissolving upon contact with water so that all of carglumic acid in the tablet can be released and dissolved in water.
CARBAGLU tablet is supplied by Orphan Europe SARL, Paris, France. Scientific discussion of European Public assessment reports (©EMEA 2004) discloses that CARBAGLU tablet is manufactured by conventional high shear wet granulation and oven drying process followed by compression to form tablets. The tablets are packed, together with a desiccant unit, in a polypropylene container, which is closed with a screwed polyethylene cap and stored in a refrigerator until use.
CARBAGLU tablet manufactured by the wet granulation and oven drying process suffers from several shortcomings. First, the CARBAGLU tablet prepared by the process is not very stable. This is probably due to the oven drying step in which carglumic acid and the excipients are subjected to a high temperature. As a result, CARBAGLU tablet is more prone to degradation. According to the package label, unopened CARBAGLU bottles should be tightly closed and stored in a refrigerator at 2-8° C. (36-46° F.). After first opening of a bottle, the bottle must be stored at a temperature above the refrigerated temperature 2-8° C. (36-46° F.) but below 30° C. (86° F.). Any unused tablets in the bottle must be discarded after one month from the first opening. Second, as with most of wet granulation processes, the problems such as sticking to the dies and rollers during the preparation of tablets may occur. Such problems are aggravated by the fact that carglumic acid is highly hygroscopic and that a high content of carglumic acid is contained in CARBAGLU tablet. Because CARBAGLU tablet is only manufactured by Orphan Europe SARL in Europe, transporting CARBAGLU tablet to the hospitals and pharmacies in the United States is very cumbersome because the stringent, low temperature requirement for storing and transporting CARBAGLU bottles must be followed during the entire importation.
The recommended initial dose for acute hyperammonemia is 100 mg/kg/day to 250 mg/kg/day. Thus, for a 70 kg patient, the daily dose will be 7,000 mg/day (35 pills/day) to 17,500 mg/day (87.5 pills/day), which translates to a medical bill of $200,000 to $400,000 per month. Typically patients suffered from deficiency of the hepatic enzyme NAGS need to take a maintenance dose of CARBAGLU tablet for life after the initial treatment of acute hyperammonemia.
Thus, there exists a need for a cost effective process for manufacturing CARBAGLU tablet. There is also a need for CARBAGLU tablet or a generic version thereof that has an improved dissolution profile and an improved stability.
It is an object of the invention to provide a simpler and more economical process for producing pharmaceutical drugs in solid dosage forms compared to conventional available process, i.e., wet granulation.
It is another object of the invention to provide a drug formulation that will yield a stable, preferably high drug content, and/or rapidly water dissolving immediate release solid dosage form.
It is a further object of this invention to provide a generic carglumic acid tablet which has improved manufacturing, dissolution, and stability properties, and is less expensive to produce, compared to the equivalent commercial product, CARBAGLU.